It is an urgent problem to establish disease prevention and therapeutic methods including infection prevention technology for mammals including humans (specifically domestic animals, pet animals, etc.), birds (specifically farmed chicken, pet birds, etc.), amphibian animals, reptiles, fish (specifically pet fish, etc.) and invertebrates. Furthermore, in order to achieve this, the methods using no chemicals, without environmental pollution, without producing resistant bacteria and without accumulation in the human body are strongly required. The present inventors have already found for the above problems that the immunopotentiators derived from natural products safely achieve disease prevention and therapeutic effects (Non-patent Document 1). As one example thereof, it is possible to use lipopolysaccharide obtained from Pantoea agglomerans which is a resident microbiota with wheat flour (Non-patent Document 1). It has been known that a limulus-positive glycolipid has a potent immunoenhancing activity (Non-patent Document 2). This limulus-positive glycolipid includes so-called lipopolysaccharide. It has been known that lipopolysaccharide is a major component of an outer wall of a cell of gram-negative bacteria as well as a major component of Coley's vaccine and has a potent immunopotentiation activity (Non-patent Document 3).
The present inventors have found that a limulus-positive glycolipid is present in wheat flour, a part thereof is lipopolysaccharide of a resident microbiota with wheat and they strongly potentiate innate immunity (Non-patent Document 4). And, the above two potentiate innate immunity safely and potently and exhibit protective and therapeutic effects on various diseases including infectious diseases by administering them percutaneously or orally (Non-patent Document 5). Furthermore, the present inventors have reported that a fermented wheat extract which is a novel immunopotentiator, not only in which the content of lipopolysaccharide derived from Pantoea agglomerans is increased, but also which contains the component derived from wheat by fermenting wheat flour with Pantoea agglomerans which is a resident microbiota with wheat flour, exerts an effect for infection prevention as a safe and trouble-free natural material in place of antibiotic substances or chemicals in the fields of animal industry and aquaculture.
A basic structure of lipopolysaccharide is composed of lipid referred to as lipid A and various types of sugars (polysaccharide) covalently bound thereto. A portion subsequent to lipid A is composed of R core which has a relatively uniform structure in related species and a subsequent O-antigen polysaccharide portion which has a different structure depending on the species (Non-patent Document 7). The O-antigen has a repeating structure of the same oligosaccharide characteristic for LPS (lipopolysaccharide) (Non-patent Document 1). Therefore, lipopolysaccharide generally forms a mixture having multiple molecular weights. It has also been known that lipopolysaccharide has a different structure depending on the microorganism which it is derived from. For example, lipopolysaccharide derived from Salmonella and lipopolysaccharide derived from Escherichia coli are different in structure and also in biological activity. However, in general, it is not easy to determine the structure of lipopolysaccharide. Thus, details of the structure and function of lipopolysaccharide in many gram negative bacteria have not been known. Thus, it has been described that lipopolysaccharide has a novel structure based on its functional difference.
Moreover, it has been demonstrated in recent studies that lipopolysaccharide activates innate immunity via TLR4 (Non-patent Document 6). It has been found that the lipid A moiety of lipopolysaccharide is essential for binding to TLR4 and a polysaccharide moiety greatly affects efficiency of intracellular signal transduction of TLR4. From the above, it is speculated that the difference in cellular response to lipopolysaccharide is attributed to a structural difference.
It is important in establishing the usefulness of lipopolysaccharide to confirm that percutaneously or orally administered lipopolysaccharide is safe and trouble-free. Thus, the gram negative bacteria used for producing and fermenting foods since ancient times have gained focus. That is, if limulus-positive glycolipid, inter alia lipopolysaccharide is present in the gram negative bacteria used for producing foods or provided for human consumption with fermented products, this fact confirms eating experience for limulus-positive glycolipid or lipopolysaccharide. This is a finding which strongly shows that percutaneously or orally administered lipopolysaccharide is safe and trouble-free, as well as encouraging the development of new health care products such as cosmetics and foods, and pharmaceuticals using these substances.
[Non-patent Document 1] Chie Kohchi et al., “Innate Immunity Regulatory Action of Fermented Wheat Extract,” New Food Industry (2006) Vol. 48, p. 19-27.
[Non-patent Document 2] Ulmer, A. J. et al., “Lipopolysaccharide: Structure, Bioactivity, Receptors, and Signal Transduction,” Trends in Glycoscience and Glycotechnology, (2000) Vol. 14, p. 53-68.
[Non-patent Document 3] Starnes, C. O., “Coley's Toxins in Perspective,” Nature, (1992) Vol. 357, p. 11-12.
[Non-patent Document 4] Nishizawa, T. et al., Chem. Pharm. Bull., (1992) Vol. 40, p. 479-483.
[Non-patent Document 5] Hiroyuki Inagawa et al., “Therapeutic and Preventive Effect of Lipopolysaccharide (LPSw) having Macrophage Activation Action and Derived from Wheat of Various Diseases,” Biotherapy, (1991) Vol. 5, p. 617-621.
(Non-patent Document 6) Kiyoshi Takeda et al., “Toll-like Receptors in Innate Immunity.,” International Immunology, Vol. 17, p. 1-14.
[Non-patent Document 7] Seikagaku Jiten 2nd Edition (1990), Tokyo Kagaku Dojin, p. 1949.